The chemical identity of the hypothalamic releasing hormone, corticotropin releasing factor (CRF), was elucidated seven years ago. It is now well established that this 41 amino acid-containing peptide is the major physiological regulator of secretion of anterior pituitary adrenocorticotropin (ACTH) and other pro-opiomelanocortin-related peptide hormones; it is, therefore, the major mechanism by which the central nervous system (CNS) controls the activity of the pituitary adrenal axis. In addition to its endocrine role, findings from this laboratory and others have provided data concordant with the hypothesis that CRF is an important neurotransmitter/neuroregulator in extrahypothalamic brain areas. The heterogeneous brain distribution of CRF and its receptors, its release from brain slices, its synaptosomal localization, its coupling with classical second messenger systems, and its potent behavioral and electrophysiological effects all support a neurotransmitter role for this peptide. The present proposal seeks to provide further evidence for a role for CRF as a CNS neurotransmitter, to determine its biochemical and molecular mechanisms of action after it binds to its receptor (second messengers, protein phosphorylation, etc.), and to further characterize the interaction of CRF with CNS noradrenergic systems. In addition, the effects of acute and chronic stressors as well as antidepressant and anxiolytic drugs on the dynamics of CRF-containing neurons will be assessed by measurement of brain concentrations of CRF and CRF mRNA levels as well as CRF receptor number, affinity and functional efficiency. In clinical studies the diagnostic specificity of the elevation in CSF CRF concentrations in major depression will be explored. Finally, in postmortem brain tissue samples from suicide victims and age- and sex-matched controls, CRF concentrations, CRF MRNA levels, CRF-stimulated cyclic AMP synthesis and CRF receptor number and affinity will be assessed. This combination of preclinical and clinical studies will provide novel information on the complex relationship between CRF, physiological responses to stress and major depression. Such basic neurobiological studies of CRF may lead to the development of novel pharmacotherapeutic agents for the treatment of affective disorders.